MEDICINAL CHEMISTRY AND RADIOCHEMISTRY CORE ABSTRACT The Medicinal Chemistry and Radiochemistry (MCRC) Core represents the central hub of activity of this U19 Center. The initial focus of the MCRC Core is the use of novel in silico methods for the identification of lead compounds for PET radiotracer development for alpha synuclein (Asyn) and 4R tau. This approach to lead compound identification is highly innovative since it has never been applied prior to this in the field of PET radiotracer development. Once in silico hits have been confirmed as true lead compounds from the radioligand binding studies conducted in Projects 1 and 2, the MCRC Core will be responsible for conducting structure-activity relationship (SAR) studies to identify compounds having the appropriate properties for radiolabeling and additional in vitro and in vivo characterization. The radiolabeling studies will be conducted by the radiochemistry component of the MCRC Core. There are four different sites involved in the MCRC Core, the University of Pennsylvania, Washington University-St. Louis, the University of Pittsburgh, and the contract research organization, MedChem Imaging. The Core Co-Directors are Drs. Robert H. Mach and E. James Petersson of Penn; each site will also have a site P.I. (C. Mathis, Pitt; Z. Tu, Wash U; Neil Vasdev, MedChem Imaging). The site P.I.s will serve as members of the Executive Steering Committee, who will meet via video teleconference on a bi-weekly basis. The goal of the Executive Steering Committee is to monitor progress of the in silico screening methods and in vitro binding studies, and the determination of which group should be assigned the resultant SAR studies on the true lead compounds. Another goal of the MCRC Core is to conduct an in vitro assay to determine if promising compounds are substrates for P-glycoprotein. A final function of the MCRC Core is to conduct scale-up synthesis of precursors and standards required for the imaging studies conducted by the Clinical Imaging Core.